Table1_The role of microRNAs in defining LSECs cellular identity and in regulating F8 gene expression.xlsx

Introduction: Coagulation Factor VIII (FVIII) plays a pivotal role in the coagulation cascade, and deficiencies in its levels, as seen in Hemophilia A, can lead to significant health implications. Liver sinusoidal endothelial cells (LSECs) are the main producers and contributors of FVIII in blood, a fact we have previously elucidated through mRNA expression profiling when comparing these cells to other endothelial cell types.
Methods: Our current investigation focuses on small microRNAs, analyzing their distinct expression patterns across various endothelial cells and hepatocytes.
Results: The outcome of this exploration underscores the discernible microRNAs expression differences that set LSECs apart from both hepatocytes (193 microRNAs at p < 0.05) and other endothelial cells (72 microRNAs at p < 0.05). Notably, the 134 and 35 overexpressed microRNAs in LSECs compared to hepatocytes and other endothelial cells, respectively, shed light on the unique functions of LSECs in the liver.
Discussion: Our investigation identified a panel of 10 microRNAs (miR-429, miR-200b-3p, miR-200a-3p, miR-216b-5p, miR-1185-5p, miR-19b-3p, miR-192-5p, miR-122-5p, miR-30c-2-3p, and miR-30a-5p) that distinctly define LSEC identity. Furthermore, our scrutiny extended to microRNAs implicated in F8 regulation, revealing a subset (miR-122-5p, miR-214-3p, miR-204-3p, and miR-2682-5p) whose expression intricately correlates with F8 expression within LSECs. This microRNA cohort emerges as a crucial modulator of F8, both directly through suppression and indirect effects on established F8-related transcription factors. The above microRNAs emerged as potential targets for innovative therapies in Hemophilia A patients.

引言：凝血因子VIII（Coagulation Factor VIII，FVIII）在凝血级联反应中发挥核心作用，其水平缺陷（如A型血友病中所见）可导致严重的健康危害。肝窦内皮细胞（Liver sinusoidal endothelial cells，LSECs）是血液中FVIII的主要产生来源与贡献者，我们此前通过将其与其他内皮细胞类型进行mRNA表达谱分析，已阐明这一关键事实。
方法：本研究聚焦于微小RNA（microRNAs），分析其在不同内皮细胞与肝细胞中的差异化表达模式。
结果：本研究的探索结果证实，LSECs与肝细胞（193个微小RNA的表达差异满足p<0.05）及其他内皮细胞（72个微小RNA的表达差异满足p<0.05）之间存在显著的微小RNA表达差异。值得注意的是，相较于肝细胞与其他内皮细胞，LSECs中分别有134个和35个微小RNA呈高表达，这一发现为解析LSECs在肝脏中的独特功能提供了重要依据。
讨论：本研究鉴定出一组可明确界定LSEC身份的10个微小RNA（miR-429、miR-200b-3p、miR-200a-3p、miR-216b-5p、miR-1185-5p、miR-19b-3p、miR-192-5p、miR-122-5p、miR-30c-2-3p及miR-30a-5p）。此外，我们进一步分析了与F8调控相关的微小RNA，发现其中一个子集（miR-122-5p、miR-214-3p、miR-204-3p及miR-2682-5p）的表达与LSECs内的F8表达存在复杂的相关性。该微小RNA群体可通过直接抑制作用，或通过影响已明确的FVIII相关转录因子产生间接效应，从而成为F8的关键调控因子。上述微小RNA有望成为A型血友病患者创新治疗的潜在靶点。